Rhinitis is a term used to describe the symptom complex related to irritation and inflammation of the nasal passageways (see, e.g., Middleton's Allergy Principles & Practice Volume II Fifth Edition Copyright 1998). Rhinitis affects 50 to 60 million Americans and the prevalence of allergic rhinitis has increased dramatically over the past 30 years.
Patients with rhinitis can experience a variety of symptoms including sneezing, rhinorrhea, nasal itching, congestion, and/or postnasal drainage. As a result, patients with these symptoms often experience headaches, fatigue, impaired concentration, reduced productivity, loss of sleep, increased occupational risk, increase in asthma, sinusitis, and otitis, and decreased emotional well being and social functioning (see, e.g., “Advice From Your Allergist” published by American College of Allergy, Asthma & Immunology, revised July 2000). Occasionally, children with chronic rhinitis develop altered facial growth and orthodontic problems. (See Table 1).
TABLE 1Symptoms and Complications of RhinitisSymptomsRhinorrheaNasal congestionSneezingPruritusPostnasal dripAdditional SymptomsHeadacheFatigueCognitive impairmentComplicationsDisturbances of facial growth and developmentDental malocclusionsOtitis mediaSinusitisDisturbance of taste and smellSleep apnea and sleep interruptionActivation of nasal-bronchial reflexesTable Source: “Clinician’s Manual on Rhinitis: Both Allergic and Nonallergic”, Published by Science Press, Copyright 2001
The financial impact is also very significant. Health care expenditures in 1996 were estimated to be 6 billion dollars and this figure does not include the indirect cost of the 3.5 million loss work days and 2 million loss school days (See, Tables 2-3).
TABLE 2Direct and Indirect Cost Estimates for Allergic Rhinitis (1994)Direct CostsAmbulatory visits301,371,342Emergency department17,730,879Total Direct Costs$1,147,258,636Office and clinic648,341,417Hospital outpatient179,814,998Indirect CostsWork-associated productivity loss46,793,667School-associated productivity loss16,656,697Restricted-activity-associated productivity loss22,959,642Total Indirect Costs$ 86,410,006Total Costs$1,233,668,642Table Source: Clinician’s Manual on Rhinitis: Both Allergic and Nonallergic, Published by Science Press, Copyright 2001
TABLE 3Medical Expenditures Attributable to Allergic Rhinitis/Conjuctivitis and Related Airway Disorders (1996 US$/Millions)Allergic rhinitis/§937.1260.5§72.6593.21863.4conjunctivitisChronic otitis 49.6540.1232.814.7326.4320.21483.5media and eustachian tube disorderSinusitis88.2436.0117.13.078.3294.61017.3Asthma523.4156.384.4§86.0156.51006.7Acute upper 12.882.330.7§36.449.1211.8respiratory infectionPhyaryngitis 7.863.721.40.136.835.9165.7and tonsilitisOther §33.216.00.320.318.288.0conjunctivitisChronic rhinitis§30.18.9§3.719.662.3Rhinorrhea§19.7§1.0§11.432.0TOTAL681.82299.0771.819.1660.51498.55930.7*Included prescribed and over-the-counter medications ordered during visits to the physician's office, hospital outpatient department or emergency department. Did not include refills. § Nonsignificant expenditures according to criteria of the National Center for Health Statistics. Table Source: “Clinician's Manual on Rhinitis: Both Allergic and Nonallergic ”, Published by Science Press, Copyright 2001
Chronic rhinitis, (rhinitis of greater than 6 weeks duration), is among the most common problem presenting to primary care physicians. Rhinitis can be caused by an allergy to inhalants, i.e., pollen, mold, animal dander and allergy to foods (58 million Americans). Non-allergic causes including strong odors, sudden temperature changes, alcohol ingestion, airborne irritants, skiing/jogging, pregnancy, spicy foods, and certain medications (e.g., topical agents such as certain alpha-adrenergic vasoconstrictors, cocaine, eye drops and oral agents such as antihypertensives, birth control pills, and certain phenothiazines) affect approximately 19 million Americans. Forty-four percent of the patients with allergic rhinitis have concomitant non-allergic rhinitis. This later group of patients with mixed rhinitis represents an estimated 26 million people in the United States. Prior to the present invention, however, there has not been an effective single entity medication for treatment and/or prevention of mixed rhinitis in patients.
The attached flowchart (See, FIG. 1) is useful in establishing a pattern for pharmacologic therapy for mixed rhinitis, which embraces an integrated approach (Figure Source: “Middleton's Allergy Principles & Practice”, Vol. n, 5111 Edition, Copyright 1998). Currently, there are many single entry topical medications for treatment of allergic rhinitis. Nasal steroids, which top the list, (See, Table 5 below) help both the immediate and late phase response by modulating the production and effects of the ever-growing family of cytokines. Recently, cytokines have been shown to playa role in non-allergic rhinitis pathophysiology as well.
The diagnosis of mixed rhinitis is made when patients are known to have allergic rhinitis but their symptoms are clearly worsened by non-allergic triggers. Mixed rhinitis is one of the more difficult entities to treat, probably because of the great variety of provocative stimuli and its unremittingly perennial nature. Patients with mixed rhinitis can also already have an iatrogenic addiction to topical decongestants (rhinitis medicamentosa), chronic sinusitis, and/or nasal polyps as a result of their long-standing illness.
Empiric treatment with a topical broad based agent that is indicated for allergic rhinitis and non allergic rhinitis is a reasonable choice for first line therapy, but most patients need immediate relief of their symptoms to reinforce their long term plan with short term relief (see, e.g., Clinician's Manual on Rhinitis: Both Allergic and Nonallergic, published by Science Press, Copyright 2001). Topical decongestants fit this need, but used alone, they can induce rhinitis medicamentosa (iatrogenic rhinitis). Botanical agents which cool the nasal membranes such as menthol, camphor and eucalyptus give an immediate sensation of improved airflow. Interestingly, this sensation occurs without any actual change in nasal airway diameter or restriction. Thus, there is a subjective feeling of improvement with immediate results from the patient's perspective gives the patient the “security” of being able to breathe more easily (see, e.g., “Asthma and Rhinitis” edited by William W. Busse, & Stephen T. Holgate, published by Blackwell Science, Copyright 1995).
When it is not possible to definitively diagnose the type of rhinitis present (i.e., allergic vs. non-allergic), emphasis on broad based treatment should be considered. At present all of these broad based treatment components are available only as single entity formulations, i.e., single entity topical steroids, single entity topical decongestants (some with cooling aromatic components), single entity topical antihistamines or topical anticholinergic agents. Thus, there is a need in the art for a fixed integrated pharmacotherapy composition which can effectively treat the allergic as well as the non-allergic components of mixed rhinitis without harmful sequella, e.g., rhinitis medicamentosa. Prior to the present invention there had been no formulation useful for treatment of acute mixed rhinitis which combined effective amounts of a suitable nasal decongestant and a suitable corticosteroid that can also be used on a long term basis without inducing long term use complications such as rhinitis medicamentosa. The cost and compliance benefits of a such a composition are also of undeniable importance.
Presently, when long-term decongestant use is indicated, physicians must rely on systemic decongestants to avoid the adverse effects of long term topical use. Systemic therapy with decongestants can also produce adverse effects including; nervousness, insomnia, irritability headache, palpitations, tachycardia, hypertension, glaucoma, and decreased urinary flow as well as sexual dysfunction in males which greatly limits the use of oral decongestants. One of the only three alpha-adrenergic agonists available, phenylpropanolomine, was recently removed from the market because of fatal cardiovascular events related to its use, further limiting this choice of therapy. With only two systemic decongestants left, the therapy dilemma is even more complicated. Accordingly, there is a need in the art for a topical composition (as provided by the present invention) which can immediately alleviate congestion and can also be used on a long term basis without the risk of developing rhinitis medicamentosa or the risk adverse effects encountered with systemic decongestant therapy. The novel compositions provided by the present invention combine the use of topical nasal decongestant with an anti-inflammatory agent (topical steroid) and substantially eliminates the risk of rhinitis medicamentosa and concomitantly eliminates the risk of systemic decongestant use.
Likewise, in animals, especially companion animals such as dogs, cats and horses, there exists a need in the art for a composition adapted for topical administration and or nebulization which can effectively treat upper respiratory conditions in patients suffering from allergies, and/or infectious/inflammatory disorders such as inflammatory airway disease (IAD) and/or mixed rhinitis and that also can be used for treatment of lower respiratory conditions, e.g., recurrent airway obstruction (heaves). In horses, especially competition animals such as racing thoroughbreds, for example, inflammatory airway disease and/or upper respiratory inflammation can be troublesome and economically devastating. Pharyngitis, sinusitis and guttural pouch inflammation and/or infection if not properly treated can become a chronic manifestation in training animals and decrease performance. Inflammatory airway disease and pharyngitis or mixed rhinitis is often observed in young athletic horses, e.g., in two year olds in training. Mechanical irritation from breathing cold air in conjunction with environmental contaminants (dust, mold spores and the like) with or without an infectious component can predispose the animal to a lingering bout with upper airway inflammation such as pharyngitis or inflammatory airway disease. Clinical signs can be subtle and are often manifested as a chronic cough, excess mucus in the trachea and poor performance. Otherwise, the animal can have a normal attitude and appetite.
Treatment approaches to upper airway disease in the horse have largely been directed at treatment of the inflammation and broncho constriction which manifest especially with IAD. Aerosolized therapy with anti-inflammatory agents such as corticosteroids has been tried via nebulization or metered dose inhalation (MDI). In addition, bronchodilators such as albuterol have been used with some measure of success and also immunostimulants and antibiotic have been advocated. Treatment of pharangitis and gutteral pouch inflammation has been directed to various throat washes and lavages such as e.g., sodium iodide with or without DMSO. These can be used in conjunction with systemic antibiotic and or corticosteroid or other systemic anti-inflammatory agents such as NSAIDs, e.g., phenylbutazone or flunixin megulamine. However, prior to the present invention there has not been a single entity medication adapted for direct topical application which utilizes a unique combination of active agents for the effective treatment of upper airway disease in animals.